Kaempferol ameliorates septic coronary microvascular injury through PHB2-PKM2 mediated mitochondria and endoplasmic reticulum homeostasis.

BACKGROUND

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are pivotal contributors to coronary microvascular injury. Traditional Chinese medicine (TCM) has shown remarkable advantages in treating coronary microvascular injury. Nevertheless, the exact mechanisms by which KA exerts its effects, especially through the Prohibitin 2 (PHB2) and pyruvate kinase M2 (PKM2) pathway for treating coronary microvascular injury in sepsis, are still not well understood. This study aims to investigate the mechanism by which KA modulates mitochondrial and ER homeostasis through the PHB2/PKM2 pathway, thereby ameliorating septic coronary microvascular injury.

METHOD: PHB2-specific knockout (PHB2cko) and transgenic (PHB2tg) mouse models, along with coronary microvascular endothelial cell models with PHB2 knockdown (siRNA-PHB2), PHB2 overexpression (ad-PHB2), PKM2 knockdown (siRNA-PKM2), and PKM2 overexpression (ad-PKM2), were utilized to explore the roles of Kaempferol in septic coronary microvascular injury.

RESULTS

KA treatment enhanced mitochondrial stability, modulated the mitochondrial quality control (MQC) system, inhibited calcium overload, and attenuated cardiac inflammation and myocardial microvascular dysfunction through the PHB2/PKM2 pathway. Molecular docking confirmed the direct interaction between PHB2 and PKM2 and the target of KA action.

CONCLUSION

KA plays a protective role against septic coronary microvascular injury by regulating MQC, inhibiting ER stress injury, and balancing mitochondria and ER homeostasis through the PHB2/PKM2 signaling pathway.